Congestive heart failure typically occurring as a result of myocardial infarction remains the leading cause of mortality from heart disease. Cardiac stem cell therapy has offered promise in animal and clinical studies, but remains inherently constrained by the logistical challenges of delivering and integrating exogenous cells into a host myocardium. The recent discovery that induced cardiomyocytes (iCMs) could be generated directly from somatic cells offers the exciting possibility of bypassing stem cell staging and, perhaps more importantly, converting scar fibroblasts in situ into iCMs, obviating entirely the challenges of cell implantation into a host myocardium. We and several others have recently demonstrated that the administration of a cardiac transcription factor cocktail (e.g., GATA4, MEF2c and TBX5 [GMT]) results in as much as a 50% increase in ventricular function, reduced fibrosis, and increased iCM populations in small animal myocardial infarction models. Intriguingly, we have also demonstrated that reductions in infarct size appear to far exceed the extent of scar repopulation with iCMs, and that GMT also appears to reduce the population of (scar-producing) myofibroblasts as well as the expression of key scar remodeling cytokines. These data, and our observation that GMT efficacy is enhanced by the angiogenic pre-treatment of myocardial scar with vascular endothelial growth factor (VEGF), suggest the existence of unexplored and non-optimized underlying mechanisms. Given our long-term goal to develop a potentially important new treatment for CHF, we propose to determine whether cellular reprogramming can be applied to improve cardiac infarct remodeling and function by testing the serial hypotheses that: a) inadequate up-regulation of requisite reprogramming genes limits cell transdifferentiation efficiency, which can be optimized beyond current thresholds via the comprehensive application of genomic activation strategies, b) that the density of (contractile) iCMs in infarct zones as well as indirect or paracrine (i.e., anti-fibroti) mechanisms play critical roles in GMT/VEGF mediated infarct remodeling, and c) that cardiac fibroblasts can be made susceptible to reprogramming in a clinically relevant fashion. We will use cutting edge molecular strategies and pre-clinical animal models to execute these aims.